Download 1 Mechanisms of chronic heart failure development

Mechanisms of chronic heart failure development in end-stage renal disease
patients on chronic hemodialysis
Jan Malik1), Vladimir Tuka1), Magdalena Mokrejsova2), Robert Holaj1), Vladimir
Tesar2),
1)
Third Department of Internal Medicine and 2)Department of Nephrology
General University Hospital, First School of Medicine, Charles University
Prague, Czech Republic
Short title: Heart failure in patients on chronic dialysis
Corresponding author:
Jan Malik, MD, PhD
Third Department ojf Internal Medicine
General University Hospital
U nemocnice 1
12808 Prague
Czech Republic
Tel./fax +420224923852
E-mail: [email protected]
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Summary:
More than 50% of end-stage renal disease (ESRD) patients treated by chronic
hemodialysis die from cardiovascular diseases, including congestive heart failure
(CHF). The incidence of CHF is rising in both general and ESRD population.
However, the mechanisms, which lead to the development of CHF in dialyzed
patients, differ considerably.
First, there are several factors leading to increase of the left ventricular afterload:
volume overload between dialyses, hypertension, increased arterial stiffness,
anemia, vascular access (arteriovenous fistula) flow and sympathetic activation.
Second, hypertension, left ventricular hypertrophy, anemia and frequently present
coronary artery disease worsen myocardial oxygenation. The combination of these
factors explains the high incidence of CHF in dialyzed patients and their roles are
reviewed in this article.
Key words: heart failure, dialysis, volume overload, pressure overload
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1. Prevalence, mortality, morbidity
More than 50% of end-stage renal disease (ESRD) subjects treated by chronic
hemodialysis die from cardiovascular diseases(Collins 2003). Congestive heart
failure (CHF) is present in more than one-third of new dialysis patients(Stack and
Bloembergen 2001) with an incidence of 71/1000 person-years. This figure is
substantially greater than the incidence of acute coronary syndromes in ESRD
patients (29/1000 person-years in US Renal Data System (USRDS) Morbidity and
Mortality Study Wave 2)(Trespalacios et al. 2003). CHF contributes significantly to
mortality and morbidity and also worsens the quality of life. For instance, the median
overall survival of ESRD patients with CHF is reported to be 36 months compared
with 62 months in patients without CHF (Harnett et al. 1995). Fewer than 15% of
dialysis patients are alive 3 years after hospitalization for CHF (Trespalacios et al.
2003).
CHF is, by definition, a state in which the heart is unable to pump blood at a rate
appropriate to the requirements of the metabolizing tissues or can do so only from an
elevated filling pressures(Zipes 2005). CHF in ESRD patients differs from CHF states
in subjects with preserved renal function by several factors. Interdialytic volume
overload and vascular access flow are specific only for ESRD. Therefore,
hemodialysis contributes also per se to the development of CHF. During continuous
worsening of chronic kidney disease, nephrogenic hypertension develops. This is the
source of pressure overload, especially in patients with inadequate hypertension
control. Most important mechanisms of CHF in ESRD patients treated by
hemodialysis are discussed below. We did not include the problems associated with
peritoneal dialysis nor kidney transplantation to keep this review more transparent.
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Increased left ventricular mass (hypertrophy) (LVH) is the most frequent cardiac
abnormality diagnosed in patients starting hemodialysis (present is as many as
80%)(Foley et al. 1995, Herzog et al. 1998). LVH is an independent and strong risk
factor for cardiovascular morbidity and mortality in both normal population(Levy et al.
1990) and in ESRD patients(Silberberg 1989). In the latter population, LVH is
principally due to an increased demand in the left ventricular minute work resulting
from volume/flow and pressure overload (Meeus et al.1989). Two forms of the left
ventricular hypertrophy could be present and are relatively equivalent in prevalence
in dialysis population: eccentric and concentric. Eccentric hypertrophy results from
volume overload leading to cardiac myocyte dropout: there is myocyte to arteriolar
capillary mismatch. Concentric hypertrophy is typically the result of hypertension and
increased afterload and is exacerbated by anemia, hyperparathyreoidism, and high
angiotensin II concentrations. In experimental renal failure, LVH was associated with
reduced capillary density and subsequent interstitial fibrosis(Mall et al. 1990, Amann
et al. 1990). The latter is probably a reason of diastolic and later also systolic
dysfunction of the left ventricle present in LVH. While in general population
hypertension is the most frequent cause of the left ventricle hypertrophy, in ESRD
patients, the correlation between left ventricle mass and blood pressure is weak, and
experimental and clinical studies have shown that hypertrophy develops even in
normotensive ESRD subjects (London et al. 1987).
Schematically, factors contributing to the development of CHF include those
increasing preload and decreasing the myocardial perfusion or oxygenation of the left
ventricle (Tab. 1). Left ventricular afterload is increased by some and decreased by
other mechanisms – Fig. 1.
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2a. Mechanisms of CHF: volume overload between dialyses
Most subjects with ESRD have insufficiently low or even no diuresis, which leads to
water retention. Excessive water is removed during dialysis sessions by ultrafiltration.
Nevertheless, dialysis is usually performed only 2- 3 times per week and body water
accumulates and fluctuates between the dialysis sessions. This fluctuation plays a
role in the development of the left ventricular hypertrophy, which in turn predisposes
to CHF (London 2003). The ultrafiltration rate is targeted to reach so called dry
weight of the patient. There are several methods of dry weight calculation. To
simplify, dry weight is the minimal tolerated weight – without clinical signs of
dehydration. Inappropriate calculation of the dry weight leads to chronic volume
overload (Charra 2007).
Overhydration between the dialyses contributes to the pathogenesis of LVH in ESRD
by its effects on blood pressure control and also by induction of volume overload
(London 2003). The internal dimensions of the left ventricle, stroke volume, and enddiastolic pressure are directly related to circulating blood volume (Chaignon et al.
1981). Body fluid volume reduction during dialysis sessions induces a decrease in left
ventricle diameter and cardiac output, and there is a direct correlation between
interdialytic body weight changes and LV mass, as well as stroke volume (Harnett
1993). LV mass is correlated with the concentration of atrial natriuretic peptides,
which are influenced by extracellular fluid volume (Zoccalli et al. 2001). Regression of
the left ventricular dimensions and LVH can be achieved by ultrafiltration and
reduced salt intake in hemodialysis patients (Ozkahya et al. 1998). Indeed, patients
treated by daily dialysis have lower and steadier levels of brain natriuretic peptide
(BNP), the marker of heart failure and overhydration (Odar-Cederlof, et al. 2006). A
similar LVH reduction was associated with better blood pressure control, decrease in
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extracellular fluid volume, and with lower volume fluctuation in patients on daily
dialysis (Fagugli et al. 2001).
2b. Mechanisms of CHF: anemia
Anemia is a frequent condition in even milder stages of chronic renal disease, mainly
due to decreased synthesis of erythropoietin. Non-hemodynamic mechanisms of
body adaptation to anemia include increased oxygen extraction in tissues, mediated
by increased 2,3-diphosphoglycerate levels. Mechanisms of hemodynamic
compensation of anemia are complex: 1. Reduced afterload due to a decrease in
systemic vascular resistance; 2. Increased preload due to an increase in venous
return; 3. Increased left ventricular function attributed to increased sympathetic
activity and inotropic factors. Increased left ventricular performance can result from
an increased preload (Frank-Starling mechanism) and from changes in inotropic state
in relation to high sympathetic activity or inotropic factors (Muller et al. 1991). In
chronic anemia, typical for ESRD, long-lasting flow/volume overload and increased
cardiac work lead to progressive cardiac enlargement and to the left ventricular
hypertrophy (Parfrey et al. 1991). The alterations in cardiac function are
accompanied by simultaneous remodelling of the large conduit arteries (London et al.
1996). Indeed, in dialysis patients, anemia is associated with LVH, left ventricular
dilatation, congestive heart failure, increased hospitalization rate, and increased
mortality(Foley et al. 1996, Ma et al. 1999, Madore et al. 1997).
In patients on dialysis, treatment of anemia with erythropoietin alters both the function
and the structure of the left ventricle. It decreases the stroke volume and heart rate,
and decreases the cardiac output and left ventricular work (Fellner et al. 1993). Older
studies showed optimistic data of mortality risk decrease (Moecks 2000). Recent
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studies compared the lower and higher target hemoglobin values (10.5-11.5 g/dl and
13.0–13.5 g/dl, respectively). They failed to show any benefit of higher target
hemoglobin value except for better quality of life (Drueke et al. 2006, Singh et al.
2006). In a meta-analysis, patients in the higher target value group had higher
mortality (Phrammintikul et al. 2007). It was speculatively explained by increased rate
of thromboses, including infarctions as a result of both higher hematocrite, and by
some direct effects of erythropoietin favoring inflammatory states.
2c. Mechanisms of CHF: hypertension and arterial wall stiffness
CKD could be both the reason and the result of hypertension. This is probably the
source of the very high hypertension prevalence in ESRD subjects. For example, in
our previous study, more than 70% of 258 subjects coming for vascular access
examination into our department from the whole country suffered from hypertension
(Malik et al. 2007). In non-ESRD patients, several studies have repeatedly confirmed
that the treatment of high blood pressure decreases both cardiac and particular
cerebrovascular events in patients with diabetes (Schrier et al. 2002) as well as in
those without diabetes(Hansson et al. 1999). Similarly, decreasing blood pressure
has been shown to prevent progression of renal disease (Bakris et al. 2000). A new
light was brought by a series of subsequent studies, which were meta-analysed by
the project “INDIANA” (Boutitie et al. 2002). It has been shown that lowering diastolic
blood pressure is protective until a certain level and then the risk of all-cause
mortality rises again: J-shaped curve. The authors have revealed a J-point at a
diastolic blood pressure of 84 mmHg. There are several possible explanations of this
phenomenon and 2 of them seem to be particularly important: 1. Subjects with low
blood pressure suffer probably from more severe cardiac disease (heart failure
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and/or coronary artery disease). 2. Because decreasing diastolic blood pressure is
associated with increasing pulse pressure (= the difference between systolic and
diastolic pressure), there is a possibility that an increment in pulse pressure may be
culpable for these findings (Berl and Henrich 2006).
The ill effects of hypertension are usually attributed to the reduction in the caliber of
arterioles, resulting in a peripheral resistance increase. Blood pressure is the easiest
measurable index of opposition to left ventricular ejection (afterload). In fact, the
appropriate term to define the arterial factors opposing LV ejection is the aortic
impedance, which depends on: 1) the peripheral resistance, 2) the viscoelastic
properties of the aorta and central arteries, and 3) the inertial forces represented by
the mass of the blood in the aorta and left ventricle (Nichols and O´Rourke 2005).
Peripheral resistance, as a determinant of mean blood pressure, sets the general
level at which the pressure wave will fluctuate. The amplitude of this fluctuation
(pulse pressure) is influenced by the viscoelastic properties of the aorta and large
arteries and by the characteristics of the left ventricular ejection (stroke volume and
ejection velocity). The viscoelastic properties of the aorta can be described in terms
of compliance, distensibility and stiffness (Meeus et al. 2000). Stiffening of arterial
walls can increase the afterload independently of peripheral resistance. Clinically,
high aortic stiffness is suspected in patients with high pulse pressure. The latter can
occur in case of diastolic pressure decrease, systolic pressure increase, or both.
Arterial stiffening leads to faster pulse wave velocity, which, after the reflections at
the level of the peripheral arteries, returns earlier to the aorta, amplifies aortic and
even ventricular pressures during systole (aortic valve is still open) and reduces
aortic pressure during diastole (Safar et al.1990). Vitious circle continues by further
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stiffening of arteries. Arterial stiffening is also a result of metabolic disturbances – see
below.
2d. Mechanism of CHF: Vascular pathology, coronary artery disease
Several vascular pathologies play a role in patients suffering from ESRD. These
include 1. atherosclerosis; 2. arteriosclerosis; 3. vascular calcifications and
remodeling.
Atherosclerosis develops rapidly in ESRD patients. Uremia produces specific
atherogenic factors, e.g. secondary form of complex dyslipidemia (Madore 2003),
calcium-phosphate metabolism alterations (Floege and Ketteler 2004), malnutrition,
and activation of inflammation (Madore 2003). These factors are additive to the risk
factors present in patients with normal renal function, such as age, hypertension,
smoking, diabetes, male gender and insulin resistance (Brunner et al. 2005).
Although atherosclerosis was considered the only cause of macrovascular disease,
many vascular complications arise in ESRD patients in the absence of clinically
significant atherosclerotic disease.
Arteriosclerosis refers to the hardening or stiffening of arteries (or arterioles). It is
typically associated with aging and involves the entire arterial tree, although it
principally affects the elastic arteries. Unlike atherosclerosis, arteriosclerosis involves
both intimal and medial thickening. Arteriosclerosis is associated with vascular
hypertrophy characterized by increased wall thickness, lumen enlargement, and
increased length of arteries, referred together as remodeling (London 2003).
Histologically, arteries from uremic patients have been reported to have fibrous or
fibroelastic intimal thickening; calcification of the internal elastic lamella, medial
ground substance and medial elastic fibers; and disruption and reduplication of the
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internal elastic lamella (Ibels et al. 1979). These indicate the predominance of arterial
calcification in uremia and provide histological evidence for the loss of elasticity in
ESRD. Excessive calcification affects also the cardiac valves.
Tunica media calcification is a common feature in ESRD subjects. Diabetes mellitus
is the strongest risk factor, but uremia per se has also been shown to contribute. It is
due to disturbed calcium/phosphate metabolism – abnormal phosphate homeostasis
in the setting of ESRD markedly alters the severity, progression, and extent of
vascular calcifications (Vattikuti et al. 2004). Vitamin D deficiency, as a result of
kidney failure, affects cardiac contractility, vascular tone, cardiac collagen content
and cardiac tissue maturation (Achinger and Ayus 2005). Reduced levels of vitamin
D, hyperphosphatemia and a tendency towards hypocalcemia lead to the increased
production of parathormone and the secondary hyperparathyreoidism develops
(DeFrancisco 2004). Clinically, so-called calcium/phosphate product is used as a
measure of calcium/phosphate metabolism. Detailed description of the mechanisms
of vascular calcifications is behind the scope of this article. Higher concentrations of
aldosterone, endothelin, angiotensin II, asymetric di-methylarginine (ADMA, which is
an endogenous inhibitor of nitric oxide-synthase) etc. also contribute to higher arterial
stiffness.
2e. Mechanism of CHF: valvular disease
Valvular calcifications are typical for ESRD patients. They mostly occur in mitral and
aortic valve and are markers of poorer prognosis. Wang et al. found that valvular
calcification is an important predictor of all-cause and cardiovascular mortality in
peritoneal dialysis patients (Wang et al. 2003). They hypothesized, that the poor
outcome could be explained by the fact that these patients have the most severe and
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advanced atherosclerosis. On the contrary, the increased mortality was not explained
by the valvular obstruction. Despite the findings of Wang et al., the incidence of aortic
valve stenosis increases during last 2 decades (Michel 1998). It is explained by
increasing age of hemodialyzed population, but disturbances of calcium/phosphate
metabolism probably also play a role together with the increased shear of aortic valve
due to hyperkinetic circulation. In a general population, aortic stenosis leads to heart
failure in its late stage. In ESRD patients, aortic stenosis could contribute to heart
failure symptoms earlier.
Mitral valve calcifications lead only rarely to the development of significant
regurgitation/stenosis.
Valvular regurgitation may be also a result of infective endocarditis. It is more
common in patients dialyzed via permanent catheter (Kamalakannan et al. 2007).
2f. Mechanism of CHF: vascular access
Surgically created vascular access, either “native” (direct connection of patient´s
artery and vein) or with the use of artificial graft, serves for repeated entries into the
blood stream during hemodialyses. Adequate flow volume is needed for the
hemodialysis procedure and also for longer patency of the access. Generally,
forearm accesses have flow 400-800 ml/min, brachial accesses 800-1500 ml/min.
Such flow is ensured by the sudden fall of peripheral vascular resistance just after the
access creation together with further maturation of both the feeding artery and
outflow vein. This systemic vascular resistance decrease leads to subsequent
volume overload and –at least temporarily- to increased cardiac output and left
ventricle ejection fraction (Ori et al. 1996). Bos et al. (Bos et al. 1999) studied the
effects of vascular accesses on cardiac oxygen supply and demand using pressure
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wave analysis. They concluded that accesses have small effect on left ventricular
oxygen demand, but decrease cardiac oxygen supply considerably.
Case reports of hyperkinetic heart failure as a result of high flow access have been
published, such as that of Jin et al.(Jin et al. 2006). More commonly, access flow
contributes to the development of already present congestive heart failure either
clinically silent or overt. Such opinion is supported by the following studies of access
creation impact on heart failure parameters: Ori et al. documented an increase of
cardiac output, ejection fraction, cardiac index and of atrial natriuretic peptide and a
decrease of plasma renin activity in a small study (10 subjects). Similar findings were
observed 2 weeks after access creation (Iwashima et al. 2002), and left ventricle
diastolic function worsened after access creation together with increase of ANP and
BNP. We observed statistically significant increase of BNP levels 6 weeks after the
construction of vascular access with “normal” flow (709 ± 311 ml/min)(unpublished
data). Unfortunately, these studies do not demonstrate the long-term effect of access
flow on heart failure.
An opposite approach was used by Chemla et al: they monitored the effect of
surgical access flow reduction on cardiac output in a group of high access flow
patients (3135+/-692 ml/min)(Chemla et al. 2007). Mean ± SD access age at
inclusion was 30±17 months and only accesses with flow volume exceeding 1600
ml/min were included. Cardiac output decreased significantly after the surgery
together with the access flow. Similar topic (but with the use of a differet flowreducing surgical technique) was studied in a case report (Murray et al. 2004). The
most interesting finding in this study is that in high-output states (induced by high flow
accesses), the necessary increase in cardiac output to sustain the high access flows
must be numerically greater than the actual access flow. This phenomenon is
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detectable also in the paper of Chemla et al, where access flow reduction of approx.
2 l/min led to cardiac output decrease of more than 3 l/min (Chemla et al. 2007). We
could hypothesize that this numerical imbalance mirrors excessive increase of
preload or, in other words, a sign of heart failure.
2g. Mechanism of CHF: other mechanisms
Hemodialysis is associated with repetitive hemodynamic instability and subsequent
myocardial ischemia, which may be due to coronary microvascular dysfunction. This
process may be also important for the development of heart failure in hemodialysis
patients (McIntare et al. 2008).
Pericardial effusions are common in ESRD patients, but only rarely significant if
chronic dialysis therapy has been established. Various arrhythmias could be present
as a result of ionic imbalance. They could contribute to the CHF by impaired left
ventricular filling. Sleep apnea is common in ESRD patients (Kimmel et al. 1989) and
leads to nocturnal hypoxemia. Malnutrition is also common and is associated with
higher risk of CHF (Foley et al. 1996). It could be estimated by the level of serum
albumin.
Kidney transplantation leads (sometimes) to the regression of the left ventricular
hypertrophy and systolic dysfunction (Parfrey et al. 1995). This phenomenon was
explained by the decrease of “uremic toxin” levels and the term “uremic
cardiomyopathy” is sometimes used to describe the complex non-coronary left
ventricular changes in ESRD patients (Gross and Ritz 2008). However, patients
treated by hemodialysis do not have real clinical signs of uremia and many so called
uremic toxins were already discovered – aldosterone, endothelin, angiotensin II,
ADMA, parathormone, cytokines, advanced glycation end-products, advanced
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oxidation protein products, etc. , see also a review in this journal (Cibulka and Racek,
2007).
3. Research and diagnostic limitations
The research, but also the clinical care, is limited especially by the fact that the
steady state of CHF in ESRD patients does not exist. Volume load changes between
dialyses could be documented by changing blood pressure, heart rate, vascular
access flow, left ventricle diameter and mass (Palecek et al. 2008), by levels of
natriuretic peptides etc. It is generally accepted that regular examinations should be
performed at least 24 hours after last hemodialysis, some authors examine just
before the next dialysis.
Conclusions
Congestive heart failure is common in ESRD patients and is associated with
substantial morbidity and mortality. It is a result of a complex of mechanisms, some
of them occurring solely in ESRD patients. Unfortunately, chronic hemodialysis
therapy cannot fully replace functioning kidneys. Detailed understanding of the
mechanisms leading to CHF could improve the outcome of ESRD.
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Fig 1. Factors influencing the left ventricle afterload
Hypertension
Increased arterial
stiffness
Interdialytic
volum e overload
Vascular access
↑
Afterload
↓
Sym pathetic
activation
Anem ia
Ultrafiltration
Endothelial
dysfunction
Afterload increasing mechanisms are listed in the left side of the figure, afterload
lowering factors on the right side.
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Table 1: Factors leading to the increase of preload and to the worsening of
myocardial oxygen supply
Interdialytic volume overload
Anemia
↑Preload
Vascular access flow
Inflammation
Coronary artery disease
↓Cardiac oxygen supply
Anemia
Hypertension
LV hypertrophy
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